title: Electron density guided fragment-based drug design--a lead generation example.
abstract: We describe here a method using protein crystallography as the sole detection tool for fragment-based lead discovery. The methodology consists of iterative design, synthesis, and X-ray crystallographic screening of three libraries of compounds. Target-specific compound design, by way of active site electron density in the presence of a bound fragment hit and the intentional lack of solution activity bias form the basis of our approach. We provide an example of this alternative fragment-based drug design (FBDD) method, detailing results from a campaign using ketohexokinase to generate a unique lead series with promising drug-like properties.
authors.affiliation: Structural Biology and Medicinal Chemistry, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Spring House, Pennsylvania, USA.
authors.forename: Marta C
authors.initials: MC
authors.lastname: Abad
authors.forename: Alan C
authors.initials: AC
authors.lastname: Gibbs
authors.forename: Xuqing
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000266:Adenylyl Imidodiphosphate / Q000378:metabolism; D020134:Catalytic Domain / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004583:Electrons; D004791:Enzyme Inhibitors / Q000737:chemistry; D005631:Fructokinases / Q000037:antagonists & inhibitors / Q000737:chemistry; D005632:Fructose / Q000378:metabolism; D006860:Hydrogen Bonding; D008958:Models, Molecular; D011485:Protein Binding; D054852:Small Molecule Libraries; D013431:Sulfates / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D013431:Sulfates; D000266:Adenylyl Imidodiphosphate; D005632:Fructose; D000255:Adenosine Triphosphate; D005631:Fructokinases; C021475:ketohexokinase